DK166714B1 - PROCEDURE FOR THE PREPARATION OF INTRANASALLY APPLICABLE Aqueous SOLUTIONS OF HUMANCAL CITONIN - Google Patents

Abstract

Pharmaceutical compositions in the form of aqueous solutions for the nasal administration of human calcitonin in meterable amounts, a process for the production of these pharmaceutical compositions and their use are described. The pharmaceutical composition contains a) a therapeutically effective amount of human calcitonin or a derivative thereof, b) viscosity-increasing swelling agents and c) an aqueous vehicle optionally containing isotonic additives and/or additional auxiliaries.

Description

in DK 166714 B1

The present invention relates to a process for the preparation of intranasally applicable aqueous solutions of human calcitonin.

Calcitonins belong to the group of adrenal gland hormones 5 and consist of long chain polypeptides with different activity. Certain calcitonins, e.g. human, salmon and eel calcium citonin, can be synthetically prepared, found as commercial products and generally used for the treatment of various diseases, e.g. Paget's disease, hypercalcaemia or osteoporosis.

10 Similar to other polypeptides, e.g.

insulin, enteral administration is problematic. Thus, calcitonins are rapidly degraded and only slowly absorbed by body fluids. Therefore, parenteral forms of administration of such active substances have so far been commonplace. These forms of administration, especially intramuscular or intravenous, are also problematic as they are only conditionally suitable for self-medication and can be painful. Therefore, there is a need for more convenient forms of administration which will allow the patient to easily self-medicate with a biodisposition of the active compound corresponding to an effective clinical treatment.

German Publication No. DE-A-3,335,086 describes nasal preparations, e.g. drops and spray, for application of calcitonin. In general, drops and sprays at 25 nasal application have the disadvantage that the fluid runs off too quickly.

In U.S. Patent No. 4,294,829, it is suggested that powdery mixtures of calcitonin and methylcellulose be applied to the nose instead of drops or sprays. Generally, the nasal use of powders is disadvantageous due to irritation effect, especially on dry mucous membranes. Furthermore, powders can only be relatively inaccurate when used, for example. should be applied nasally with a spray applicator.

In the disclosure of European Patent Application No. 183,527, intranasal calcitonin preparations containing 35 different absorbents such as benzyl alcohol, ethanol, thiamines, salicylic acid, capric acid, polyethylene glycols, pyridoxal, malonic acid and pyrophosphoric acid are described. As adjuvants are listed methyl and methyl hydroxypropyl cellulose in combination with these absorbents without specifying an exact composition.

In the specification of GB patent application No. 2,142,335, intranasal oily preparations of calcitonin derivatives are described. While the adjuvant carboxymethyl cellulose is mentioned together with other swelling agents, however, this publication does not mention nasal aqueous formulations 10 with these adjuvants.

In the specification of French Patent Application No. 2,312,260, formulations with human calcitonin are described. Carb oxymethyl cellulose is mentioned by virtue of its property as an adjuvant to increase viscosity. There are no 15 references to nasal application. The suspensions and solutions for which the complete composition is indicated are for intramuscular and subcutaneous application only.

In the description of European patent application no.

No. 205,627 discloses intranasal calcitonin preparations. The calcitonin itself is not specified. Absorbents are referred to as absorbents. In addition to the surfactants, cellulose ether swelling agents may be added.

In the published disclosure to Japanese patent application Sho-611-126014, viscous aqueous solutions of calcitonin, e.g. salmon calcitonin, which contains hydroxypropyl cellulose as swelling agent. Using human calcitonin, these solutions formed by adding the calcitonin to a hydroxypropyl cellulose solution are associated with disadvantages: In "Helvetica Chimica Acta" (P. Sieber et al.), Volume 53, Issue 8 (1970), No. 255, pages 2135-2150, especially pages 2141-2142, describes the formation of associates, especially fibrils, of human calcitonin in aqueous solution. Such associates decrease the resorption capacity of the human calcitonin.

Surprisingly, it has been found that the formation of fibrils can be avoided by sterile filtration of an aqueous solution of synthetic human calcitonin, lyophilization and dissolution of the lyophilisate in aqueous solution and pharmaceutical preparations in the form of an aqueous solution can be prepared. solution for 5 nasal administration of synthetic human calcitonin in readily dosable amounts.

Accordingly, the present invention relates to a process for the preparation of intranasally applicable aqueous solutions of human calcitonin containing: a) a therapeutically effective amount of synthetic human calcitonin, b) methylcellulose or methylhydroxypropylcellulose 15, as a viscosity enhancing carrier, and curing agent, and curing agent and to provide isotonic conditions, and the process of the invention is characterized by dissolving synthetic human calcitonin in water, optionally while adding the auxiliaries to obtain isotonic conditions, adjusting the solution to a pH of 4-6, sterilizing the solution and preparing a lyophilisate added to the carrier liquid containing methyl cellulose or methyl hydroxypropyl cellulose.

The general concepts used above and hereinafter in connection with the present invention preferably have the following meanings:

Methyl cellulose and methyl hydroxypropyl cellulose have an average molar substitution degree (MS) greater than one and less than three, and an average degree of polymerization of 100-5000.

The degree of substitution is an expression of hydroxy group substitution by low alkoxy groups (here methoxy groups) per

35 glucose unit. The average degree of molar substitution (MS) is an average value which indicates the number of low alkoxy groups (here methoxy groups) per million. glucose unit in the polymer.

The average degree of polymerization (GP) is also an average value which indicates the average.

5 number of glucose units in the cellulose polymer.

Preferably, methyl cellulose with GP = 200-1000 and MS = 1.4-2.0 and methyl hydroxypropyl cellulose with GP = 200-1000 and MS = 1.4-2.0 are used.

The carrier liquid has a pH value less than 6 which, after 10 dissolution of the determined amount of the active calcitonin lyophilisate, is adjusted to the determined amount of liquid. After dissolving the active substance, the pH of the carrier liquid may be between 3 and 6.

The carrier liquid preferably contains additives 15 to obtain isotonic conditions, e.g. ionic additives such as sodium chloride, or nonionic additives such as sorbitol, mannitol or glucose (carrier) in the usual concentration of isotonic solutions, e.g. as stated in 20 "Hager," Vol Vila, pages 225-239. In particular, as the carrier liquid, calcium-free, isotonic sodium chloride or sorbitol solutions are used.

The carrier liquid may further contain other pharmaceutically acceptable additives, e.g. preservatives, such as benzalkonium chloride, or surfactants to improve the flowability, especially nonionic surfactants from the group of polyoxyalkylene ethers of higher alcohols, e.g. with the general formula

RO-E (CH2) n-o4-xH

wherein RO is the hydrophobic group of a higher alcohol, e.g. lauryl or cetyl alcohol, of an alkyl phenol or of a sterol, e.g. lanosterol, dihydrocholesterol or cholesterol, as well as mixtures of two or more such ethers.

5 DK 166714 B1

Preferred polyoxyalkylene ethers are polyoxyethylene and polyoxypropylene ethers having hydrophobic groups (i.e., wherein n of the above formula is 2 or 3), especially lauryl, cetyl and cholesterol polyoxyethylene and polyoxypropylene ethers, as well as 5 mixtures of two or more such ethers.

The hydroxy groups at the terminal alkylene group of the above-mentioned polyethers may be fully or partially acylated, e.g. with acyl groups of aliphatic carboxylic acids, such as e.g. acetic acid.

Preferred polyethers have a hydrophilic-lipophilic ratio (HLB group number) of 10-20, especially 12-16.

Particularly suitable polyethers have an average value for repeating units in the polyoxyalkylene portion (the unit in parentheses of the above formula) between 4 and 75, especially between 8 15 and 30, and most preferably between 16 and 26. The polyethers can be prepared by known methods. A large selection of such products are available as trading products and are available, for example, from the company Amerchol under the trademark "Solulan" ®, from the companies KAO Soap, ICl and Atlas under the trademarks "Emalex" ®, 20 "Brij" ® and "Laureth" ® and from the company Croda under the trademark "Cetomacrogol" ®.

In addition, suitable surfactants are, in particular, non-ionic surfactants of the fatty acid polyhydroxy alcohol esters such as sorbitan monolaurate, oleate, stearate or palmitate, sorbitan stearate or trioleate, polyoxyethylene addition products of fatty acid polyhydroxy alcohol esters such as polyethylene monolaurate, oleate, stearate, palmitate, tristearate or trioleate, polyethylene glycol fatty acid esters such as polyoxyethyl ethyl stearate, polyethylene glycol 400-30 stearate, polyethylene glycol 2000 stearate, especially ethylene oxide propylene oxide copolymers of the type "® (Wyandotte).

The carrier liquid may also contain other pharmaceutically acceptable additives, e.g. essential oils for improving the odor, e.g. menthol, paraffin or glycerol 35 to improve the flowability, sugar and / or sweeteners to enhance the taste, and flavors.

DK 166714 B1 e

The nasal application of the pharmaceutical compositions allows for a comfortable and simple administration of human calcitonin by the patient himself, so that the usual usual parenteral administration by the treating physician can be avoided.

The pharmaceutical compositions are characterized by good compatibility and long residence time of the active substance at the site of application. The high viscosity of the aqueous solution to be applied causes a long residence time of the 10 mucous membranes and thus a very good resorption of the active substance.

The aqueous solution for nasal application containing synthetic human calcitonin lowers plasma calcium and plasma phosphate levels in the blood of warm-blooded animals and humans and can therefore be used to treat hypercalcaemia and / or bone disorders such as Paget's disease or osteoporosis.

The dose of human calcitonin to be applied and the concentration of the active ingredient in the pharmaceutical composition depend on the disease to be treated and on the condition of the patient.

The resorption of human calcitonin (determined as blood plasma concentration) is surprisingly high after nasal administration. Even higher values can be obtained than the corresponding 25 values determined after intramuscular injection. The amount of dose to be administered may constitute a multiple of the known dose amounts which are, for example, customary for intramuscular administration.

Heretofore, single doses of approx. About 30 minutes have been administered by subcutaneous or intramuscular injection of human calcitonin. 0.5 mg of active substance once a day to 3 times a week. The nasal administration in question during the treatment period requires doses of 1.0-10.0 mg at a frequency of once daily to approx. 3 times a week. The above doses can be applied by a single administration, ie. in the treatment, single nasal doses containing 1.0-10.0 mg of synthetic human calcitonin are administered.

7 DK 166714 B1

Optionally, this dose amount can also be distributed over 2-4 administrations per day. day. The total volume of the compositions for the nasal administration is preferably 0.1-0.5 ml.

The invention preferably relates to a process for the preparation of a pharmaceutical composition in the form of an aqueous solution for the nasal application of synthetic human calcitonin having a viscosity range of 20-300 mPasek (25 ° C). This pharmaceutical composition contains: a) a therapeutically effective amount of synthetic human calcium citonin, b) 0.2-3.0% by weight methylcellulose or methylhydroxy-propylcellulose (GP = 200-1000, MS = 1.4-2.0 ) and c) the carrier fluid with the excipients to achieve isotonic conditions.

The invention relates primarily to a process for preparing a pharmaceutical composition in the form of an aqueous solution for the nasal application of synthetic human human calcitonin having a viscosity range of 20-100 mPasek (25 ° C). This pharmaceutical composition contains: a) a therapeutically effective amount of synthetic human calcitonin, b) 0.5-1.0% by weight of methylcellulose or methylhydroxy-propylcellulose (GP = 200-1000, MS = 1.4-2.0) and c) the carrier fluid with adjuvants to achieve isotonic conditions.

In a preferred embodiment of the process, the lyophilizate of the synthetic human calcitonin is prepared, for example, by dissolving the calcitonin in the necessary amount of nonionic additives to obtain isotonic conditions (carrier forms), e.g. mannitol, in distilled water, sets the solution with dilute aqueous base, e.g. sodium hydroxide solution, at a pH of 4- DK, sterile filters the solution on which it is lyophilized. The lyophilisate containing active substance is added to a solution (mucous) containing methyl hydroxypropyl cellulose or methyl cellulose and optionally other additives such as sorbitol and preservative such as benzalkonium chloride. This slimy solution can be applied to the nose by a dropper.

The pharmaceutical compositions are preferably isotonic, whereby the osmotic pressure can vary between 260 and 380 10 mOsm / kg.

The desired viscosity range can be set by adding appropriate amounts of component b). If the viscosity is too low, the liquid will run away too quickly. If the viscosity is too high, the liquid becomes chewy and difficult to apply.

Aqueous solutions with 0.2-3% methylcellulose or methylhydroxypropylcellulose (GP = 200-1000, MS = 1.4-2.0) have a particularly good viscosity. The corresponding viscosities are at 20 ° C in the range of 5-5000 mPasek, especially 20-300 mPasek, most preferably 20-100 mPasek (25 ° C). Reference is made to the exact specifications set forth in "Hager", Vol. VII, pages 115-118, which describe the preparation of aqueous solutions of the desired viscosity as a function of the concentration of the viscosity-increasing quenchant. By the addition of the active substance, salts, surfactants 25 and other additives, the viscosity values of the pure solutions with swelling agents can be changed. In general, the viscous solutions should have sufficient flowability and ensure adequate wetting of the nasal mucosa.

The liquid administration form prepared by the method of the invention may be administered nasally to the patient in the usual manner with a droplet pipette. The patient can take the solution himself in the prescribed amount. The pharmaceutical compositions may also be prepared in situ, e.g. by mixing a lyophilizate of the calcitonin with a previously prepared solution containing no active substance, but containing a swelling agent and additives, before use, e.g. with methyl cellulose or methyl hydroxypropyl cellulose and sorbitol or sodium chloride and then apply the mixture nasally.

The process of the invention is further illustrated in the following examples. Temperatures are given in eC.

Example 1 a) Preparation of active lyophilisate substance

Components 10 "CIBACALCIN" ® 10.0 mg

Mannitol 10 mg 10 mg of "CIBACALCIN" ® (human calcitonin) and 10 mg mannitol are dissolved at room temperature under nitrogen in 2.0 ml of distilled water. The pH is adjusted by approx. 4 mg IN aqueous NaOH to 4.5. The solution is sterile filtered with a sterile membrane filter (0.2 μπι pore size) and the sterile solution is filled into a sterile vial. The vial is frozen at -40 ° and lyophilized in a freeze-drying apparatus.

b) Preparation of a solution containing nitrogen

Components 25 "Methocel" ® 90 HG 4000 cP 50.0 mg

Sorbitol 500.0 mg

Benzalkonium chloride 1.0 mg

Distilled water 10.0 mg of methyl hydroxypropyl cellulose ("Methocel" ®), sorbitol and benzalkonium chloride are mixed in distilled water. The solution is quenched for several hours at 5 ° and then the viscous solution is filtered with a "Scrynel" ® filter with a pore size of 10 μια. The filtered solution is filled into a vial and sterilized, e.g. in an autoclave. The pH of the sterilized solution is 6-7.

C) Preparation or application of 11 CIBACALCIN113-nasal solution (2.0 ml cibacalcinlvophilisate / 0.4 ml solution containing swelling agent) In vials of the 5 active lyophilisate prepared in Example 1 a) are dissolved in 2.0 ml of the solvent containing swelling agent according to Example 1 (b). The pH of the solution corresponds to that of the lyophilisate. 0.4 ml of the slimy "CIBACALCIN" ® solution is applied to the lying patient's nose (both nostrils) with a dropper.

10

Example 2 a) Analogously to Example 1 a), active lyophilizates of 10 mg "CIBACALCIN" ® (without mannitol addition), 10 mg "CIBACALCIN" ® with 30 mg mannitol and 10 mg 15 "CIBACALCIN" ® with 10 mg can be prepared. mannitol and 2 mg of methyl hydroxypropyl cellulose ("Methocel" ®), thereby regulating the pH of the solution to be lyophilized with a dilute aqueous sodium hydroxide solution to a pH between 3.5 and 6.0.

B) Analogously to Example 1 b), solutions containing swelling agents of 20-100 mg of methyl hydroxypropylcellulose ("Methocel" ®), 500 mg of sorbitol and 1.0 mg of benzalkonium chloride or of 20-100 mg of hydroxypropylcellulose ("Klucel") can be prepared ), 500 mg of sorbitol and 1.0 mg of benzalkonium chloride.

C) Analogously to Example 1 c) A solution containing swelling agent with the compositions of Example 2 b) is mixed with an active lyophilizate substance with the compositions of Example 2 a) and nasal application is made.

30

Claims (4)

A process for the preparation of intranasally applicable aqueous solutions of human calcitonin containing 5 a) a therapeutically effective amount of synthetic hura calcitonin, b) methylcellulose or methylhydroxypropylcellulose as viscosity enhancing swelling agent, c) carrier liquid, with any other auxiliary liquid, by dissolving synthetic human calcitonin in water, optionally with the addition of the excipients to obtain isotonic conditions, adjust the solution to a pH of 4-6, sterile filter, prepare a lyophilisate and add it to the carrier liquid containing methylcellulose or methylhydroxypropylcellulose . Process according to claim 1, characterized in that synthetic human calcitonin is dissolved in water containing mannitol as an adjuvant to achieve isotonic conditions. Process according to claim 1 or 2, characterized in that the lyophilisate is added to the carrier liquid containing 0.2-3% by weight of methylcellulose or methylhydroxypropylcellulose. 4. A process according to claim 1 or 2, characterized in that the lyophilisate is added to the carrier liquid containing 0.5-1.0% by weight of methylcellulose or methylhydroxypropylcellulose.